Bridging Project 1: Conformational Transitions in P-class ATPases
桥接项目 1:P 类 AT 酶的构象转变
基本信息
- 批准号:7922841
- 负责人:
- 金额:$ 23.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAttentionBindingCationsCell surfaceCellsChargeComputing MethodologiesCore ProteinCouplingCrystallographyCytoplasmic TailCytosolEnzymesEukaryotaFaceFluorescence Resonance Energy TransferFree EnergyHydrolysisIndividualIon TransportIonsKineticsLocationMeasurementMeasuresMediatingMembraneMembrane ProteinsMethodsModelingMolecular ConformationMovementMuscle CellsN DomainNatureOocytesPathway interactionsPhosphorylationPhysiologicalProkaryotic CellsPumpReactionRelative (related person)ResolutionSarcoplasmic ReticulumSeriesSiteSite-Directed MutagenesisSquidStructural ModelsStructureTestingTrefoil MotifXenopus oocytebasecomputer studiesconformational conversiondesigninorganic phosphateluminescence resonance energy transfermembermembrane fluxprotonationresearch studysingle-molecule FRETtime usevoltagevoltage clamp
项目摘要
P-class (or E1-E2-type) ATPases constitute a superfamily of cation transport enzymes, present both in prokaryote and eukaryote, whose members mediate membrane flux of all common biologically relevant cations [1]. P-class pumps use ATP to transport ions against a gradient. The sarcoplasmic reticulum Ca+ -ATPase (SERCA) pumps 2 Ca+ from the cytosol of muscle cells to the sarcoplasmic reticulum by exchanging H"". In each normal cycle, the Na/K pump transports 3 Na" out of the cell by 2 K = into the cell
at the expense of the hydrolysis of one molecule of ATP. This extended bridge project about P-class ATPases represents the combination of two bridge projects, focused on the Na/K and SERCA pumps.
From crystallographic snapshots of SERCA and the recently solved first crystal structure of the Na/K pump, we now dispose of a remarkable series of pictures showing how these enzymes look at different states of their transport cycle. SERCA is now by far the membrane protein where the most functionally different conformations have been described in precise structural detail [4, 5]. However, electrophysiological studies with SERCA are harder to do than with the Na/K pump, which can be expressed heterologously on the surface of cells. For this reason, while structural information about the Na/K pump is more limited (with only one x-ray structure available), the most informative functional analysis comes from experiments on the Na/K pump.
In this proposal, we address questions about the Na/K and SERCA pumps: What are the conformational dynamics involved as the pump transits through conformational states revealed by x-ray crystallography?
What is the nature of the coupling between the binding of ATP, phosphorylation, and the movements of charged species across the core of the protein? What are the stepwise voltage-sensitive steps? What is the complete reaction pathway and what are the individual transition rates under various physiological conditions? Answers to these questions will correlate the structural changes to the function of membrane P-class ATPase pumps.
P 类(或 E1-E2 型)ATP 酶构成了阳离子转运酶的超家族,存在于原核生物和真核生物中,其成员介导所有常见生物学相关阳离子的膜通量[1]。 P 级泵使用 ATP 逆梯度输送离子。肌浆网 Ca+ -ATP 酶 (SERCA) 通过交换 H"" 将 2 Ca+ 从肌肉细胞的细胞质泵送到肌浆网。在每个正常循环中,Na/K 泵将 3 Na" 从细胞中输送 2 K = 进入细胞
以一分子 ATP 的水解为代价。这个关于 P 级 ATP 酶的扩展桥项目代表了两个桥项目的组合,重点关注 Na/K 和 SERCA 泵。
从 SERCA 的晶体快照和最近解决的 Na/K 泵的第一个晶体结构,我们现在处理了一系列引人注目的图片,显示这些酶如何看待其运输周期的不同状态。目前,SERCA 是一种膜蛋白,其功能上最不同的构象已得到精确的结构细节描述 [4, 5]。然而,SERCA 的电生理学研究比 Na/K 泵更难进行,Na/K 泵可以在细胞表面异源表达。因此,虽然有关 Na/K 泵的结构信息更加有限(只有一种 X 射线结构可用),但信息最丰富的功能分析来自 Na/K 泵的实验。
在本提案中,我们解决了有关 Na/K 和 SERCA 泵的问题:当泵穿过 X 射线晶体学揭示的构象状态时,涉及哪些构象动力学?
ATP 结合、磷酸化和带电物质穿过蛋白质核心的运动之间的耦合本质是什么?什么是逐步电压敏感步骤?完整的反应途径是什么?各种生理条件下的个体转化率是多少?这些问题的答案将结构变化与膜 P 类 ATP 酶泵的功能联系起来。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FRANCISCO J BEZANILLA其他文献
FRANCISCO J BEZANILLA的其他文献
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洪堡巨轴突中钠钾泵的电荷易位
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Charge translocation by the sodium-potassium pump in the giant axon of the Humbol
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